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Obstet Gynecol Clin N Am 34 (2007) 403419

Current Management of Ectopic Pregnancy


Liberato V. Mukul, MD*, Stephanie B. Teal, MD, MPH
Department of Obstetrics and Gynecology, University of Colorado at Denver and Health Sciences Center, Academic Oce 1, B198-2, 12631 East 17th Avenue, P.O. Box 6511, Aurora, CO 80045, USA

Ectopic pregnancy, which is any pregnancy implanted outside the uterine cavity, remains the leading cause of pregnancy-related rst-trimester death among women in the United States. Fertilization of the ovum occurs in the fallopian tube. As the zygote divides, it becomes rst a morula and then a blastocyst, normally arriving in the uterine cavity and beginning implantation on day 6 after fertilization. Anything that delays or impedes tubal transport may allow implantation to begin while the blastocyst is still in the tube; approximately 97% of ectopic pregnancies are tubal in location. Ectopic pregnancies represent approximately 2% of all pregnancies [1,2]. This estimate is conservative, as the analysis did not include patients whose condition was diagnosed and managed exclusively as outpatients. While the incidence of ectopic pregnancy has continued to increase, the case fatality rate has dropped from 69% in 1876 [3], to 0.35% in 1970, and to 0.05% in 1986. The death rate for African American and other minority women remains over double that for white women, and the highest death rate occurs in the 15- to 19-year-old age group [4]. With documented intrauterine pregnancy, the risk of coexisting ectopic (heterotopic pregnancy) is approximated at 1 case in 10,000 patients to 1 case in 30,000 [5,6]. This risk increases to approximately 1 case in 100 patients if the woman is being treated for infertility [7]. Risk factors Risk factors for ectopic pregnancy are strongly associated with conditions that cause alterations to the normal mechanism of fallopian tubal
* Corresponding author. E-mail address: liberato.mukul@uchsc.edu (L.V. Mukul). 0889-8545/07/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ogc.2007.07.001 obgyn.theclinics.com

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transport. It is postulated that the more damage that occurs to the fallopian tube, the higher the risk for developing an ectopic pregnancy. This damage may result from a number of factors, such as infection, surgery, congenital anomalies, or tumors. Many potential risk factors have been reported in the literature, some with good evidence and others with less convincing data. There is good evidence to support the following as risk factors for developing an ectopic pregnancy: history of previous ectopic pregnancy, previous tubal surgery, tubal ligation, tubal pathology, in utero diethylstilbestrol exposure, and current use of an intrauterine device (IUD) [8]. In a 1996 meta-analysis, Ankum and colleagues [8] reported an odds ratio of 6.6 (95% CI, 5.28.4) with a history of a previous ectopic pregnancy. Barnhart and colleagues [9] in 2006 conrmed previous reports that a history of previous ectopic pregnancy was the strongest risk factor associated with ectopic pregnancy. A history of one previous ectopic pregnancy conferred an odds ratio of 2.98 (95% CI, 1.884.73) and a history of two ectopic pregnancies increased the risk to 16% overall (odds ratio 16.04; 95% CI, 5.39 47.72). Table 1 presents a comparison of the odds ratios evaluated in these two studies. Reconstructive tubal surgery has also been shown to be a high risk factor for ectopic pregnancy with an odds ratio of 4.7 [8]. Reconstructive tubal surgery is closely linked to the underlying tubal damage caused by a previous ectopic pregnancy or pelvic inammatory disease. The complexity of surgical restoration of the damaged tube correlates with subsequent risks of developing an ectopic pregnancy [10]. The underlying risk factors, and not the surgery itself, are the likely major contributing factors in these cases. Patients who have undergone tubal reanastomosis are also at risk for ectopic pregnancy. In one study, 6.6% of patients were diagnosed with an ectopic pregnancy after undergoing tubal reanastomosis. The same study also found that patients who had a history of tubal occlusion by cautery were at higher risk than those who had reversals after noncautery methods [11]. Tubal ligation failures also confer a high risk for ectopic pregnancy. The US Collaborative Review of Sterilization prospectively followed 10,863 women electing tubal sterilization. Thirty-three percent of post-sterilization pregnancies occurring in this population (47 out of 143 pregnancies) were ectopic; all but 1 were tubal. The risk was highest in patients who had a tubal ligation using bipolar cautery, and in women sterilized under the age of 30. The risk of ectopic pregnancy in these patients was 31.9 per 1000 procedures compared with 1.2 per 1000 procedures in patients who had a postpartum salpingectomy [12]. The increased risk with bipolar cautery is most likely associated with stula formation of the fallopian tube leading to subsequent failure. There are currently no data on the risk of ectopic pregnancy after hysteroscopic sterilization. The use of both hormonal and nonhormonal contraceptive methods confers protection against ectopic pregnancy [13]. This includes the use of both hormonal and nonhormonal IUDs. However, should a patient get pregnant

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Table 1 Risk factors for ectopic pregnancy Risk factor High risk factor Previous ectopic pregnancy Previous tubal surgery History of tubal ligation In utero DES exposure Current use of IUD Moderate risk factor History of PID History of infertility Smoking History of gonorrhea History of chlamydia Weak or no association Outpatient treatment chlamydia/gonorrhea Sexual partners O1 Coitarche !18y Past use of IUD History of TAB Nontubal surgery Prior cesarean section Ankum (odds ratio; 95% CI) 6.6; 5.28.4 Barnhart (odds ratio; 95% CI) 2.9; 1.94.7 (if O2 ectopic pregnancies: 16.0; 5.447.7) Not reported Not reported Not reported Not reported 1.5; 1.12.1 Not reported Not reported See below See below 1.22; 0.62.6 Not reported Not reported 1.1; 0.61.9 0.99; 0.61.6 0.95; 0.671.4 Not reported

4.7; 2.49.5 9.3; 4.918.0 5.6; 2.413.0 4.245.0 2.5; 2.13.0 2.521.0 2.5; 1.83.4 2.9; 1.94.4 2.8; 2.04.0 Not reported 2.1; 1.44.8 1.6; 1.12.5 1.6; 1.41.8 1.6; 1.01.6 1.5; 1.12.6 0.56; 0.31.1

Abbreviations: DES, diethylstilbestrol; PID, pelvic inammatory disease; TAB, threatened abortion; Adapted from Ankum WM, Mol BW, Van der Veen F, et al. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril 1996;65(6):10939; and Barnhart KT, Sammel MD, Gracia CR, et al. Risk factors for ectopic pregnancy in women with symptomatic rst-trimester pregnancies. Fertil Steril 2006;86(1):3643.

while using an IUD, her risk of an ectopic pregnancy rises dramatically, with reported odds ratios of 4.2 to 45 [13,14]. Some studies have reported a potentially small increased risk of ectopic pregnancy in past users of an IUD, but more current, well-controlled research indicates there is no increased risk with previous IUD use [9,13]. Previous genital tract infection is the major cause of tubal damage and infertility. A history of previous cervical infection with Neisseria gonorrhea or Chlamydia trachomatis and pelvic inammatory disease has been linked to increased risk for ectopic pregnancy [8,15]. A recent study found that a previous history of pelvic inammatory disease had an odds ratio of 1.5 (95% CI, 1.112.05) for ectopic pregnancy [9]. This study specically looked at patients treated for N gonorrhea or C trachomatis in the outpatient setting versus those requiring inpatient treatment for pelvic inammatory disease. The investigators found that patients who received outpatient treatment

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for N gonorrhea and/or C trachomatis did not have an increased risk for ectopic pregnancy (odds ratio 1.22; 95% CI, 0.62.6). These ndings suggest that the insult to the normal tubal transport mechanism may be greater when patients present with symptoms or ndings that require inpatient management. Hillis and colleagues [15] reported that repeated chlamydia infections increased the risk for ectopic pregnancy. The odds ratio after two infections was 2.1 and rose to 4.5 after three infections. A history of nontubal pelvic surgery has been inconsistently reported to confer a potential increased risk for ectopic pregnancy [1618]. Barnhart and colleagues [9] in 2006 found no strong association for nontubal surgery (including cesarean section) and ectopic pregnancy. In addition, there was also no association between a history of voluntary interruption of pregnancy (therapeutic abortion), regardless of number, and ectopic pregnancy. This study did not mention appendectomy as a risk factor, but in another study, a history of an appendectomy was more commonly reported in cases of ectopic pregnancy [19]. Diethylstilbestrol exposure in utero has been shown to confer a ninefold increased risk of ectopic pregnancy [20]. Other potential risk factors include smoking, young age at coitarche, multiple sexual partners, vaginal douching, and infertility [8,21]. Many of these risk factors likely act through a common pathway of tubal damage by infectious or environmental agents.

Location The most common location for an ectopic pregnancy is in the fallopian tube. Other less common sites include the abdomen, ovary, cervix, and the interstitial portion of the fallopian tube. In one study, over 95% occurred in the fallopian tube in the following locations: ampulla (70%), isthmus (12%), mbria (11.1%), and interstitium/cornua (2.4%). The remaining sites of ectopic pregnancies were ovarian (3.2%), abdominal (1.3%), and cervical (!1%) [22]. Identifying the location of an ectopic is important for therapy, but may be very challenging. Ultrasound remains the best method to diagnose location. The location of an ectopic pregnancy may alter the approach to treatment and subsequent follow-up. Depending on location, a combination of medical and surgical treatment may need to be employed. This review will focus on the management and treatment of tubal ectopic pregnancy.

Presentation The classic triad of abdominal pain, amenorrhea, and vaginal bleeding should always alert the clinician to evaluate for an ectopic pregnancy. Unfortunately the diagnosis may be quite challenging because the presentation of an ectopic pregnancy can vary signicantly. In one study, the percentage

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of patients who presented with ectopic pregnancy with abdominal pain was 98.6%, amenorrhea 74.1%, and irregular vaginal bleeding 56.4%. Abdominal tenderness (97.3%) and adnexal tenderness (98%) were the most common physical ndings [23]. Barnhart and colleagues [9] reported an increased odds ratio for ectopic pregnancy in patients presenting with rst-trimester symptoms if moderate to severe bleeding (odds ratio 1.42; 95% CI, 1.041.93) and pain (odds ratio 1.42; 95% CI, 1.061.92) were present. Although these signs and symptoms are common, the clinical presentation of ectopic pregnancy can vary signicantly from the classic presentation. Physical examination ndings may also reveal a change in vital signs, such as tachycardia or orthostatic changes; cervical motion tenderness; adnexal/uterine tenderness (from blood irritating the peritoneal surfaces); or a palpable mass. Physical examination ndings may also be unremarkable or subtle. Ectopic pregnancy can also mimic other conditions, such as spontaneous abortion, early pregnancy failure, ruptured corpus luteal cyst, and infection. Thus, in the setting of a positive pregnancy test, ectopic pregnancy should always be high on the clinicians dierential diagnosis. In clinical scenarios of patients with known high risk factors for ectopic pregnancy, some investigators have advocated early screening for ectopic pregnancy once they have a positive pregnancy test [24]. Diagnosis Early diagnosis can reduce the mortality and morbidity associated with ectopic pregnancy. Following the history and physical examination, the two most important diagnostic tests in evaluating for an ectopic pregnancy are transvaginal ultrasound (TVUS) and a serum human chorionic gonodatrophin (hCG) level. The sensitivity and specicity of combining these tests has been reported to range from 95% to 100% [2527]. The rst step in the diagnosis of an ectopic pregnancy is to evaluate for an intrauterine pregnancy. Conrmation of an intrauterine pregnancy almost denitively rules out an ectopic pregnancy; the risk of a heterotopic pregnancy is one for every 10,000 to 30,000 spontaneous pregnancies [5,6]. However, in the setting of assisted reproductive technologies the risk can rise to 1% [7]. TVUS can identify intrauterine pregnancy at a gestation of 5.5 menstrual weeks at nearly 100% accuracy [28]. At 4.5 to 5 weeks, the rst ultrasound marker of intrauterine pregnancy is a gestational sac with a double decidual sign (double echogenic rings around the sac) [29]. The yolk sac appears next at 5 to 6 weeks and remains until about 10 weeks. The embryo (fetal pole) and cardiac activity can be rst detected at about 5.5 to 6 weeks. A potentially confounding ultrasound nding is a pseudosac. This is described as a collection of uid within the endometrial cavity that is usually localized centrally within the uterus. This can be potentially mistaken for an intrauterine gestational sac. A pseudosac is the result of endometrial bleeding from decidualized endometrium in the setting of an extrauterine pregnancy

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[30]. Unfortunately, identication of a pseudosac is not diagnostic of an ectopic pregnancy, has a high false-positive rate, and thus cannot be relied on to make the diagnosis of an ectopic pregnancy [31]. In the absence of a reliable last menstrual period, the hCG level is instrumental in the evaluation of ectopic pregnancy. The concept of a discriminatory zone should be used to help facilitate ultrasound ndings. The discriminatory zone is dened as the level of hCG at which an intrauterine pregnancy should be visualized. With abdominal ultrasound, most radiologists use 6500 mIU/ mL, but this has been further rened with the use of TVUS, reducing the discriminatory zone to 1500 to 2500 mIU/mL [30,32]. The exact cuto to use depends on the success of the institution in diagnosing the discriminatory zone, the quality of the equipment, and the expertise of the sonographer. When the hCG level has reached the discriminatory zone and an intrauterine pregnancy cannot be diagnosed, an extrauterine pregnancy should be highly suspected. An exception to this would be in cases of multiple gestations. Patients at risk for multiples, such as those using assisted reproductive technologies, can be carefully followed to a higher discriminatory zone [33]. The detection of an abnormally rising or declining hCG has also aided in the diagnosis of an ectopic pregnancy. Kadar and colleagues [34] rst reported on the concept of a doubling hCG in normal pregnancies every 1.4 to 2.1 days, with a minimum 66% rise in 2 days. More recently the hCG curves have been redened. The lower limit of a normal rise for a normal pregnancy has been reported to be 53% in 2 days. A rise lower than this is highly suggestive of an abnormal pregnancy [35]. While abnormally rising hCG levels are useful to distinguish an abnormal pregnancy, normally rising hCG levels do not rule out ectopic pregnancy. The same researchers recently reported hCG proles for women diagnosed with an ectopic pregnancy. They reported that the number of women with ectopic pregnancy who experienced a rise in hCG (60%) was similar to those with a decrease in hCG (40%) and that there was no denitive way to characterize the pattern of hCG for women with an ectopic pregnancy [36]. In situations where there is no denitive ultrasound diagnosis of an intrauterine pregnancy and the hCG level is above the discriminatory zone, uterine evacuation is indicated to dierentiate between an early pregnancy failure (miscarriage) and an ectopic pregnancy. In these cases, women have an equal chance of being diagnosed either with a miscarriage or ectopic pregnancy [37]. The same study reported that the presumed diagnosis of ectopic pregnancy was incorrect nearly 40% of the time. The addition of uterine evacuation to the treatment algorithm (Fig. 1) can help minimize the inadvertent administration of methotrexate to patients with early pregnancy failures without a signicant dierence in complication rates or cost [38]. Uterine evacuation is superior to Pipelle endometrial biopsy in the diagnosis of ectopic pregnancy and should be the method employed [39]. In the absence of chorionic villi, an ectopic pregnancy is likely and medical or surgical treatment is indicated.

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Pregnant with cramping/bleeding, hemodynamically stable

Ultrasound

EP

Nondiagnostic

Viable IUP

Abnormal IUP

Treat

Quant hCG > DZ

Quant hCG < DZ

PNC

D&C

D&C

- CV

+ CV

Serial hCG

Treat EP Normal rise TVUS when hCG>DZ

Normal fall Close monitoring

Abnormal rise

Resolution IUP PNC EP Treat Abnormal IUP D&C - CV Nondiagnostic D&C

+ CV

Treat EP

Fig. 1. Evaluation of the symptomatic rst-trimester pregnancy. CV, chorionic villi; D&C, dilation and curettage; DZ, discriminatory zone; EP, ectopic pregnancy; IUP, intrauterine pregnancy; PNC, prenatal care.

The usefulness of a single progesterone level to diagnose ectopic pregnancy has been debatable. During the rst 8 to 10 weeks, progesterone is produced by the corpus luteum and remains relatively stable. A progesterone level above 25 ng/mL is usually consistent with a normal pregnancy (97% sensitivity), while a progesterone level less than 5 ng/mL has been shown to be 99% specic in conrming an abnormal pregnancy. Unfortunately, the lower limit cannot dierentiate between an early pregnancy failure and an ectopic pregnancy [40]. In 1998, a meta-analysis of 26 studies concluded that progesterone alone is not sucient to diagnose ectopic pregnancy with good reliability [41]. Treatment After the diagnosis is made, several factors inuence the decision to treat an ectopic pregnancy medically or surgically. If the patient is unstable, then immediate surgical treatment via laparotomy or laparoscopy is necessary. In

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the past, laparotomy with salpingectomy was considered the gold standard, but with the availability of minimally invasive technology and increasing physician skill, laparoscopy is now the treatment of choice [42]. Laparoscopy is associated with a faster recovery, shorter hospitalization, reduced overall costs, and less pain, bleeding, and adhesion formation. In a hemodynamically stable patient, surgery is still the preferred route for heterotopic pregnancy, tubal rupture, or imminent risk of rupture. Other indications for surgery include no desire for or an inability to comply with medical treatment, contraindication to methotrexate, and failure of medical treatment. Surgery should also be considered for patients with conditions that seem to predispose to failure of medical therapy, such as a tubal pregnancy greater than 5 cm or fetal cardiac activity seen on TVUS [43,44]. These factors are considered in more detail below.

Salpingectomy versus salpingostomy Once the decision is made to proceed to the operating room, the surgeon must decide on the appropriate surgical technique. Often this decision must be made in the operative suite. Thus, appropriate preoperative counseling is important. Taking into consideration risk factors, patient desire for future fertility, and the condition of the patient also helps guide the intraoperative decision. Salpingectomy is the segmental or entire removal of the fallopian tube. The indications for removing the tube include recurrent ectopic pregnancy in the same tube, a severely damaged tube, uncontrolled bleeding (before or after salpingostomy), heterotopic pregnancy, and lack of desire to bear more children. Salpingostomy is the method of choice in women of reproductive age who wish to preserve their fertility. Salpingostomy is typically performed by making an incision on the antemesenteric border of the fallopian tube at the point of maximal distension. The use of vasopressin before incision has been reported to reduce bleeding and operative time in some studies, but has also been found to not be signicant in others [45,46]. Removing the product of conception by hydrodissection is recommended, along with avoiding excessive handling of the tube and excessive cautery to prevent potential further damage to the fallopian tube. The rate of intrauterine pregnancy is improved in patients having linear salpingostomy versus salpingectomy, although the recurrent ectopic pregnancy rate is also higher [4749].

Persistent ectopic pregnancy One of the potential hazards of conservative surgical management of ectopic pregnancy with salpingostomy is persistent ectopic pregnancy. The risk of persistent ectopic pregnancy after salpingostomy is reported to be

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2% to 11% with laparotomy and 5% to 20% with laparoscopy [32,50]. The increased rate in patients treated by laparoscopy is thought to be associated with the learning curve of laparoscopy. Because of the potential risk of tubal rupture and hemorrhage, some investigators recommend following weekly hCG serum levels to ensure complete resolution [51]. If the hCG level plateaus, methotrexate is usually indicated as the rst option, followed by salpingectomy if medical treatment fails. Some investigators have advocated the use of prophylactic methotrexate after salpingostomy to reduce the risk of persistent ectopic pregnancy [52,53]. Risk factors for salpingostomy failure, such as an ectopic pregnancy less than 2 cm, or rapidly rising preoperative hCG levels, may help guide the decision to administer prophylactic methotrexate after salpingostomy [54]. Small masses, by preventing complete evacuation of the ectopic pregnancy, may potentially place patients at higher risk for persistent ectopic pregnancy.

Medical management Before the mid-1980s treatment for ectopic pregnancy was exclusively surgical. The rst case report of methotrexate for the treatment of ectopic pregnancy appeared in 1982 [55]. Many other agents have been used with varying rates of success. Prostaglandins, dactinomycin, etoposide, hyperosmolar glucose, anti-hCG antibodies, potassium chloride, and mifepristone have all been described in the literature [56]. Methotrexate has been the most successful method of medical management for ectopic pregnancy and is currently the medical treatment of choice. Methotrexate for ectopic pregnancy was proposed after the observation that actively replicating trophoblasts in gestational trophoblastic disease were successfully treated with methotrexate [57]. Methotrexate is a folinic acid antagonist that binds to the catalytic site of dihydrofolate reductase inhibiting the synthesis of purines and pyrimidines, thus interfering with the synthesis of DNA and cell replication [58]. Hemodynamically stable patients are eligible for medical management with methotrexate. The inclusion and exclusion criteria for administration of methotrexate are listed in Boxes 1 and 2 [59]. The initial treatment regimens for ectopic pregnancy consisted of multiple doses of methotrexate with citrovorum rescue. Stovall and colleagues [60] in 1989 demonstrated a success rate of 96% with their multiple-dose regimen. Their protocol consisted of intramuscular methotrexate, 1 mg/kg of actual body weight alternating with citrovorum rescue factor 0.1 mg/kg. Methotrexate was continued only until there was a 15% decline in the level of hCG. These investigators then observed that most of their patients treated with the multidose regimen had declining levels of hCG before receiving the second and/or third dose of methotrexate [61]. This led to the publication of the development of the single-dose regimen without citrovorum rescue [62]. Table 2 describes the

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Box 1. Criteria for receiving methotrexate Absolute indications  Hemodynamically stable without active bleeding or signs of hemoperitoneum  Patient desires future fertility  Nonlaparoscopic diagnosis  Patient able to return for follow-up care  General anesthesia poses risk  Patient has no contraindications to methotrexate Relative indications  Unruptured mass 3.5 cm at greatest dimension  No fetal cardiac activity  b-hCG limit does not exceed a predetermined value (615 K)
Adapted from American College of Obstetricians and Gynecologists (ACOG). Medical management of tubal pregnancy. Int J Gynaecol Obstet 1999;65:99; with permission.

single-dose methotrexate regimen. The single-dose protocol uses 50 mg/m2 of patient body surface area, administered intramuscularly. Lipscomb [63] later reported the University of Tennessees experience with their rst 315 patients treated with single-dose methotrexate and reported an overall success rate of 91.1%.

Single-dose versus multidose protocol There is currently no consensus as to which methotrexate protocol should be used [59]. The overall success rate reported in the literature for both protocols is approximately 90% [64]. In a recent randomized trial of 108 patients, the success rate with a single dose was 88.9% compared with 92.6% for multidose patients [65]. This was not considered statistically signicant (odds ratio 0.64; 95% CI, 0.172.1) and no dierences in side eect proles were reported. In a systematic review, women treated with the single-dose regimen were reported to have a higher failure rate (odds ratio 4.74; 95% CI, 1.7712.62) [66]. The data obtained for this review were from case series and not randomized controlled studies. In addition, it is dicult to ascertain whether there may have been selection bias between patients receiving single- versus multidose regimens. The review did conrm that success was inversely associated with hCG levels for both protocols. Given the current available data, the single-dose methotrexate protocol appears to have similar ecacy and side eect prole while making the least impact on resources of patients and providers.

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Box 2. Contraindications to medical therapy Absolute  Breastfeeding  Immunodeciency  Abnormal creatinine (>1.3 mg/dL), aspartate aminotransferase (twice the normal value)  Alcoholism or liver disease  Preexisting blood dyscrasias  Peptic ulcer disease  Active pulmonary disease  Known sensitivity to methotrexate Relative  Gestational sac >3.5 cm  Cardiac activity
Adapted from American College of Obstetricians and Gynecologists (ACOG). Medical management of tubal pregnancy. Int J Gynaecol Obstet 1999;65:99; with permission.

Predictors of success Various predictors of success with methotrexate have been reported in the literature. Limited and anecdotal evidence has attributed success partially or entirely to such factors as hCG levels, ectopic size, fetal cardiac activity, progesterone levels, and free peritoneal blood in the cul-de-sac. Lipscomb and colleagues [44] reviewed their experience and reported that high hCG and progesterone levels and, the presence of fetal cardiac activity, were associated with higher failure rates. They further concluded that the single best predictor for success with methotrexate was the initial hCG level. In counseling patients who receive a single-dose methotrexate regimen, it is important to consider the available data on failure rates (Table 3). Patients with an hCG below 5000 mIU/mL had the best success with methotrexate.
Table 2 Single-dose methotrexate protocol Day 0 1 4 7 Therapy hCG dilation and curettage hCG, aspartate aminotransferase, serum urea nitrogen/creatinine, complete blood cell count, Rh, methotrexate (50 mg/m2) hCG hCG

Data from Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol 1991;77(5):7547.

414 Table 3 Success rates by hCG Serum b-hCG !1000 10001999 20004999 50009999 10,00014,999 O15,000

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Success rate 98% 93% 92% 87% 82% 68% (118/120) (40/43) (90/98) (39/45) (18/22) (15/22)

Data from Lipscomb GH, McCord ML, Stovall TG, et al. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999;341(26): 19748.

Patients with hCG levels between 5000 mIU/mL and 9999 mIU/mL had failure rates of 13%, increasing to 18% with an hCG between 10,000 mIU/mL and less than 14,999 mIU/mL. Above 15,000 mIU/mL, the failure rates rose to 32%. This study also concluded that a large ectopic and the presence of free peritoneal blood were not associated with higher failure rates. There is currently no set dened limit above which methotrexate should not be administered, but based on available data, the higher failure rates with hCG levels above 5000 mIU/mL need to be taken into consideration. Surveillance Once the decision is made to proceed with medical management, it is important to counsel patients about potential side eects (Box 3) and the need for close follow-up. The day of methotrexate administration is considered day 1 (see Table 2). Patients receiving the single-dose protocol then need to follow up on day 4 and 7 for additional laboratory draws and reevaluation. The day-4 hCG level can plateau or rise before a decrease begins. It is not uncommon to see a rise in the day-4 hCG level because of the continued production of hCG from syncytiotrophoblasts, despite cessation of hormone in the cytotrophoblast [67]. A study looking at the predictability of day-4 hCG on success of methotrexate found no association with success of treatment or the need for potential surgical intervention [68]. Many patients (33%60%) also experience abdominal pain (separation pain) 3 to 7 days after administration of methotrexate [48,69,70]. Separation pain is thought to be secondary to tubal abortion or an expanding hematoma within the fallopian tube [71]. This is usually self-limited and most patients can be managed conservatively with nonsteroidal anti-inammatory agents. Patients who report no relief with supportive measures should be immediately evaluated to rule out tubal rupture. The majority of methotrexate-treated ectopic pregnancies can be associated with an increase in size by TVUS, likely representing hematoma formation within the tube. This nding does not reliably predict treatment failure unless other signs of rupture are present [72,73].

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Box 3. Side effects associated with methotrexate Drug related  Nausea  Vomiting stomatitis  Gastric distress  Dizziness  Reversible alopecia (rare)  Severe neutropenia (rare)  Pneumonitis  Vaginal bleeding  Increase in abdominal pain  Increase in hCG levels from day 1 to day 4
Data from American College of Obstetricians and Gynecologists (ACOG). Medical management of tubal pregnancy. Int J Gynaecol Obstet 1999;65:97103.

Signs of treatment failure include signicantly worsening abdominal pain (despite change in hCG levels), signs of hemodynamic instability, less than a 15% decline between day-4 and day-7 hCG levels, and increasing or plateauing hCG levels after the rst week of treatment [59]. In a study of ruptured ectopic pregnancies, tubal rupture was encountered more frequently in women with no previous history of ectopic pregnancies [74], suggesting that surveillance of patients at presumed lower risk should be just as diligent as for patients with known risk factors. The same study also reported a rupture rate of greater than 11% in patients with hCG levels less than 100 mIU/mL. If no signs of treatment failure are present by day 7 and there is a decline of 15% between day 4 and day 7, weekly hCG levels are recommended until complete resolution (hCG !15 mIU/mL) is seen [61,63]. If on day 7 the drop in hCG is not greater than 15% from day 4, and if the patient is clinically stable, a second dose of methotrexate with weekly follow-up is suggested. In general, a second dose is needed in 15% to 20% of patients, with less than 1% requiring more than two doses [63,66]. The average time to resolution (hCG !15 mIU/mL) for patients successfully treated with single-dose methotrexate was 33.6 days [63].

Expectant management Expectant management of ectopic pregnancy has been employed with rates of reported in the range of 48% to 100%. That large gap in rates is in part due to the dierences in inclusion criteria [48,75]. In one study, expectant management was most successful (32 of 33) in women with hCG

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levels less than 175 mIU/mL [76]. In subjects with hCG greater than 175 mIU/mL, only 41 out of 74 were managed successfully. In a situation of a clinically stable patient with hCG less than 175 mIU/mL, indeterminate TVUS, and declining hCG levels, it may be reasonable to employ expectant management. On the other hand, given the low complication rate of methotrexate, many clinicians opt for medical treatment over expectant management.

Summary While mortality from ectopic pregnancy has dropped precipitously because of improved diagnostic and management techniques, it remains a signicant gynecologic emergency, and delay in diagnosis or treatment can be catastrophic. Diagnosis rests on maintaining a high index of suspicion for women with symptomatic complaints in the rst trimester, or women without complaints but with risk factors, such as a prior ectopic pregnancy, an IUD in situ, or pregnancy following assisted reproductive technology. Algorithms, such as that shown in Fig. 1, identify how combined use of hCG measurement, TVUS, and examination of uterine contents after conrming nonviability may be used to eciently prevent underor over-treatment. Choice of the best management technique, ranging from expectant, to outpatient medication, to conservative versus radical surgery, is based on the patients clinical condition; factors related to the ectopic, such as size, evidence of rupture, or rate of hCG rise; and the patients wishes.

References
[1] Ectopic pregnancydUnited States, 19901992. MMWR Morb Mortal Wkly Rep 1995; 44(3):468. [2] Grimes DA. The morbidity and mortality of pregnancy: still risky business. Am J Obstet Gynecol 1994;170(5 Pt 2):148994. [3] Classic pages in obstetrics and gynecology. John Stubbs Parry. Extra-uterine pregnancy: its causes, species, pathological anatomy, clinical history, diagnosis, prognosis, and treatment. Am J Obstet Gynecol 1974;118(1):136. [4] Lawson HW, Atrash HK, Saftlas AF, et al. Ectopic pregnancy in the United States, 19701986. MMWR CDC Surveill Summ 1989;38(2):110. [5] Reece EA, Petrie RH, Sirmans MF, et al. Combined intrauterine and extrauterine gestations: a review. Am J Obstet Gynecol 1983;146(3):32330. [6] Condous G. Ectopic pregnancydrisk factors and diagnosis. Aust Fam Physician 2006; 35(11):8547. [7] Ludwig M, Kaisi M, Bauer O, et al. Heterotopic pregnancy in a spontaneous cycle: do not forget about it! Eur J Obstet Gynecol Reprod Biol 1999;87(1):913. [8] Ankum WM, Mol BW, Van der Veen F, et al. Risk factors for ectopic pregnancy: a metaanalysis. Fertil Steril 1996;65(6):10939.

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